Calcipotriene, (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19), 22-tetraene-1α,3β,24-triol, is a known antipsoriatic analog of vitamin D analog having structure I.

The synthesis of calcipotriene requires many synthetic steps in which undesired side products are obtained. Therefore, the final product can be contaminated not only with side product derived from the last synthetic step of the process but also with compounds that were formed in previous steps. These side products are usually excluded by purification methods such as chromatography, triturating, and crystallization. Purification by chromatography is a frequently used purification method. Because the unwanted products are often structural isomers of the desired final product, it is almost impossible to get the desired separation and, hence, purity of the drug.
Depending on the method used to synthesize calcipotriene, different minor unwanted compounds can accompany the final product. Thus, applying conditions developed by Barton and Hesse, J. Org. Chem. 51, 1637 (1987), C-1 hydroxylation is effected with selenium dioxide accompanied by N-methylmorpholin N-oxide as a reoxidant to give 1-α-hydroxylation and about 15% of 1-β hydroxylation, of which about 0.2-1% remains in the final product after chromatographic steps. One of the most unavoidable by-products obtain during thermal cheletropic extrusion of SO2 is the C-20 epimer.
Vitamin D analogs like calcipotriene are known to be light-sensitive and this may lead to cis-trans isomerization at the 5,6 bond. Since vitamin D analogs like calcipotriene are heat sensitive, the appropriate solvent for purification is characterized by a low boiling point. According to the published literature, the most commonly used solvent is methyl formate (b.p. 32° C., threshold limit value 5000 ppm). Alcoholic solvents such as methanol, ethanol, and isopropanol (IPA) have not proved suitable because calcipotriene is highly soluble in these solvents. The reverse situation is encountered with highly apolar solvents (e.g. hydrocarbons) in which calcipotriene is essentially insoluble. Other solvents, which can be candidates for purification (e.g. recrystallization) are acetone, ethyl acetate, and mixtures of them. The drawback to these solvents is their high boiling points, which can translate to high residual solvent in the calcipotriene drug substance.
Since the solubility of calcipotriene in methyl formate is low, about Ig calcipotriene/150 mL of methyl formate, the crystallization of significant quantities of calcipotriene from methyl formate is performed using huge quantities of solvent. Moreover, to obtain reliable yield, one needs to concentrate the solution to about 1:90. This situation raises many technological and engineering problems. Recrystallization from methyl formate is also time consuming, increasing the chances that impurities will be formed.
Another important parameter influenced by the recrystallization process is the crystal size of the calcipotriene drug substance. The need to control the particle size distribution (PSD) can often pose a significant challenge in the crystallization process development. The PSD of an active pharmaceutical ingredient (API) has a dramatic impact on the formulation of drugs, especially for hydrophobic compounds, which have limited solubility in aqueous systems. When methyl formate is used for the recrystallization of calcipotriene, the particle size can arrive to 70 micron (μ), which is much bigger than the desired size. One can obtain smaller particle size by increasing stirring rate, but this approach usually leads to filtration problems, as the material stocked on the reactor. Consequently, much material is lost.
Clearly, there is a need for purification methods for calcipotriene that use much smaller volumes of solvent whilst achieving the desired purity and particle size.
Crystallization is known to be the simplest process that can be used for purification of organic compounds. Moreover, in the vitamin D family there are undesired compounds, which can be excluded only by crystallization. This is particularly true in the case of calcipotriene.
We have now found a crystallization process using a binary mixture of solvents to obtain pure calcipotriene with certain crystal size.